Mitochondrial DNA
Mitochondrial DNA (mtDNA) is a small amount of genetic material within mitochondria, containing 37 genes crucial for energy production, and mutations in mtDNA are associated with a range of health conditions, particularly those affecting high-energy tissues.
Overview
Mitochondria are structures within cells that convert the energy from food into a form that cells can use. Each cell contains hundreds to thousands of mitochondria, which are located in the fluid that surrounds the nucleus (the cytoplasm). Although most DNA is packaged in chromosomes within the nucleus, mitochondria also have a small amount of their own DNA. This genetic material is known as mitochondrial DNA or mtDNA. In humans, mitochondrial DNA spans about 16,500 DNA building blocks (base pairs), representing a small fraction of the total DNA in cells.
Mitochondrial DNA contains 37 genes, all of which are essential for normal mitochondrial function. Thirteen of these genes provide instructions for making enzymes involved in oxidative phosphorylation. Oxidative phosphorylation is a process that uses oxygen and simple sugars to create adenosine triphosphate (ATP), the cell's main energy source. The remaining genes provide instructions for making molecules called transfer RNA (tRNA) and ribosomal RNA (rRNA), which are chemical cousins of DNA. These types of RNA help assemble protein building blocks (amino acids) into functioning proteins.
Health Conditions Related to Mitochondrial DNA Changes
Age-related hearing loss
Changes in mitochondrial DNA are among the best-studied genetic factors associated with age-related hearing loss. This form of hearing loss develops with age and can begin as early as a person's thirties or forties. It typically affects both ears and worsens gradually over time, making it difficult to understand speech and hear other sounds. This condition results from a combination of genetic, environmental, and lifestyle factors, many of which have not been identified.
As people age, mitochondrial DNA accumulates damaging mutations, including deletions and other changes. This damage results from a buildup of harmful molecules called reactive oxygen species, which are byproducts of energy production in mitochondria. Mitochondrial DNA is especially vulnerable because it has a limited ability to repair itself. As a result, reactive oxygen species easily damage mitochondrial DNA, causing cells to malfunction and ultimately to die. Cells that have high energy demands, such as those in the inner ear that are critical for hearing, are particularly sensitive to the effects of mitochondrial DNA damage. This damage can irreversibly alter the function of the inner ear, leading to hearing loss.
Cyclic vomiting syndrome
Some cases of cyclic vomiting syndrome, particularly those that begin in childhood, may be related to changes in mitochondrial DNA. This disorder causes recurrent episodes of nausea, vomiting, and tiredness (lethargy). Some of the genetic changes alter single DNA building blocks (nucleotides), whereas others rearrange larger segments of mitochondrial DNA. These changes likely impair the ability of mitochondria to produce energy. Researchers speculate that the impaired mitochondria may affect certain cells of the autonomic nervous system, which is the part of the nervous system that controls involuntary body functions such as heart rate, blood pressure, and digestion. However, it remains unclear how these changes could cause the recurrent episodes characteristic of cyclic vomiting syndrome.
Cytochrome c oxidase deficiency
Mutations in at least three mitochondrial genes can cause cytochrome c oxidase deficiency, which is a condition that can affect several parts of the body, including the muscles used for movement (skeletal muscles), the heart, the brain, or the liver.
The mitochondrial genes associated with cytochrome c oxidase deficiency provide instructions for making proteins that are part of a large enzyme group (complex) called cytochrome c oxidase (also known as complex IV). Cytochrome c oxidase is responsible for the last step in oxidative phosphorylation before the generation of ATP. The mtDNA mutations that cause this condition alter the proteins that make up cytochrome c oxidase. As a result, cytochrome c oxidase cannot function. A lack of functional cytochrome c oxidase disrupts oxidative phosphorylation, causing a decrease in ATP production. Researchers believe that impaired oxidative phosphorylation can lead to cell death in tissues that require large amounts of energy, such as the brain, muscles, and heart. Cell death in these and other sensitive tissues likely contribute to the features of cytochrome c oxidase deficiency.
Kearns-Sayre syndrome
Most people with Kearns-Sayre syndrome have a single, large deletion of mitochondrial DNA. The deletions range from 1,000 to 10,000 nucleotides, and the most common deletion is 4,997 nucleotides. Kearns-Sayre syndrome primarily affects the eyes, causing weakness of the eye muscles (ophthalmoplegia) and breakdown of the light-sensing tissue at the back of the eye (retinopathy). The mitochondrial DNA deletions result in the loss of genes that produce proteins required for oxidative phosphorylation, causing a decrease in cellular energy production. Researchers have not determined how these deletions lead to the specific signs and symptoms of Kearns-Sayre syndrome, although the features of the condition are probably related to a lack of cellular energy. It has been suggested that eyes are commonly affected by mitochondrial defects because they are especially dependent on mitochondria for energy.
Leber hereditary optic neuropathy
Mutations in four mitochondrial genes, MT-ND1, MT-ND4, MT-ND4L, and MT-ND6, have been identified in people with Leber hereditary optic neuropathy. These genes provide instructions for making proteins that are part of a large enzyme complex. This enzyme, known as complex I, is necessary for oxidative phosphorylation. The mutations responsible for Leber hereditary optic neuropathy change single amino acids in these proteins, which may affect the generation of ATP within mitochondria. However, it remains unclear why the effects of these mutations are often limited to the nerve that relays visual information from the eye to the brain (the optic nerve). Additional genetic and environmental factors probably contribute to vision loss and the other medical problems associated with Leber hereditary optic neuropathy.
Leigh syndrome
Mutations in one of several different mitochondrial genes can cause Leigh syndrome, which is a progressive brain disorder that usually appears in infancy or early childhood. Affected children may experience delayed development, muscle weakness, problems with movement, or difficulty breathing.
Some of the genes associated with Leigh syndrome provide instructions for making proteins that are part of the large enzyme complexes necessary for oxidative phosphorylation. For example, the most commonly mutated mitochondrial gene in Leigh syndrome, MT-ATP6, provides instructions for a protein that makes up one part of complex V, an important enzyme in oxidative phosphorylation that generates ATP in the mitochondria. The other genes provide instructions for making tRNA molecules, which are essential for protein production within mitochondria. Many of these proteins play an important role in oxidative phosphorylation. The mitochondrial gene mutations that cause Leigh syndrome impair oxidative phosphorylation. Although the mechanism is unclear, it is thought that impaired oxidative phosphorylation can lead to cell death in sensitive tissues, which may cause the signs and symptoms of Leigh syndrome.
Maternally inherited diabetes and deafness (MIDD)
Mutations in at least three mitochondrial genes, MT-TL1, MT-TK, and MT-TE, can cause mitochondrial diabetes and deafness (MIDD). People with this condition have diabetes and sometimes hearing loss, particularly of high tones. The MT-TL1, MT-TK, and MT-TE genes provide instructions for making tRNA molecules, which are essential for protein production within mitochondria. In certain cells in the pancreas (beta cells), mitochondria help monitor levels of blood glucose, also called blood sugar. In response to high levels of glucose, mitochondria help trigger the release of a hormone called insulin, which controls blood glucose levels.
The MT-TL1, MT-TK, and MT-TE gene mutations associated with MIDD slow protein production in mitochondria and impair their function. Researchers believe that the disruption of mitochondrial function lessens the mitochondria's ability to help trigger insulin release. In people with MIDD, diabetes results when the beta cells do not produce enough insulin to regulate blood glucose effectively. Researchers have not determined how mutations in these genes lead to hearing loss.
Mitochondrial complex III deficiency
Mutations in the MT-CYB gene found in mitochondrial DNA can cause mitochondrial complex III deficiency. When caused by mutations in this gene, the condition is usually characterized by muscle weakness (myopathy) and pain, especially during exercise (exercise intolerance). More severely affected individuals may have problems with other body systems, including the liver, kidneys, heart, and brain.
The MT-CYB gene provides instructions for making a protein called cytochrome b. This protein is one component of complex III, one of several complexes that carry out oxidative phosphorylation. Most MT-CYB gene mutations involved in mitochondrial complex III deficiency change single amino acids in the cytochrome b protein or lead to an abnormally short protein. These cytochrome b alterations impair the formation of complex III, severely reducing the complex's activity and oxidative phosphorylation. Damage to the skeletal muscles or other tissues and organs caused by the lack of cellular energy leads to the features of mitochondrial complex III deficiency.
Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS)
Mutations in at least five mitochondrial genes, MT-ND1, MT-ND5, MT-TH, MT-TL1, and MT-TV, can cause the characteristic features of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). Some of these genes provide instructions for making proteins that are part of a large enzyme complex, called complex I, that is necessary for oxidative phosphorylation. The other genes provide instructions for making tRNA molecules, which are essential for protein production within mitochondria.
One particular mutation in the MT-TL1 gene causes more than 80 percent of all cases of MELAS. This mutation, written as A3243G, replaces the nucleotide adenine with the nucleotide guanine at position 3243 in the MT-TL1 gene.
The mutations that cause MELAS impair the ability of mitochondria to make proteins, use oxygen, and produce energy. Researchers have not determined how changes in mitochondrial DNA lead to the specific signs and symptoms of MELAS. They continue to investigate the effects of mitochondrial gene mutations in different tissues, particularly in the brain.
Myoclonic epilepsy with ragged-red fibers (MERRF)
Mutations in at least four mitochondrial genes, MT-TK, MT-TL1, MT-TH, and MT-TS1, can cause the signs and symptoms of myoclonic epilepsy with ragged-red fibers (MERRF). These genes provide instructions for making tRNA molecules, which are essential for protein production within mitochondria.
One particular mutation in the MT-TK gene causes more than 80 percent of all cases of MERRF. This mutation, written as A8344G, replaces the nucleotide adenine with the nucleotide guanine at position 8344 in the MT-TK gene.
Mutations in the MT-TK, MT-TL1, MT-TH, and MT-TS1 genes impair the ability of mitochondria to make proteins, use oxygen, and produce energy. It remains unclear how mutations in these genes lead to the muscle problems and neurological features of MERRF.